Our research focuses on the phosphoinositide 3-kinase (PI3K) family of proteins in the maintenance of cardiovascular health and in the progression of cardiovascular disease. The objective of this research proposal is to better understand intracellular signaling mechanisms and cellular consequences of 3-hydroxy-3-methylgultaryl (HMG) coenzyme A (CoA) reductase inhibitors (statins) mediated by PI3K. Specific PI3K isoforms mediate distinct functions. For example, in the heart, PI3K can stimulate both pathologic and physiologic responses and the key to this apparent discrepancy appears to be based upon which PI3K isoform is activated. The specific aims in this proposal will test the hypothesis that the stimulation of a PI3K isoform or subset of isoforms leads to distinct cell-signaling events in response to simvastatin that are independent of lipid-lowering. The approach will be to address the cellular mechanism of PI3K activation by simvastatin through the use of adenoviral constructs that over-express mutated PI3K isoforms. The role of PI3K in Ca2+ mobilization, activation or inactivation of downstream pathways, and cholesterol-sensitive gene transcription in response to simvastatin will be evaluated. Findings from this work will contribute to the understanding of simvastatin-induced, non lipid-lowering PI3K mediated pathways in human coronary artery endothelium and to significant improvement of current statin treatment.